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How to cope with a brain tumor

Glioma, Medicine

In the world has developed new ways to combat gliomas.
Glioma is an abnormal growth of the tumor structure in the human brain tissue. This formation is represented by a set of very different cells, it is a "heterogeneous tumor" in the terminology of scientists. Features of glioma consider it a different origin from other tumors and the absence of metastasis. However, its tumor cells have the ability to migrate to healthy brain tissue, which greatly complicates its treatment. Glioblastoma is the most aggressive stage of glioma.

Traditional approaches: surgical removal of the tumor, radiation method and chemotherapy, unfortunately, do not prolong the life of patients. Surgical intervention does not allow to completely remove tumor cells, because, firstly, a neurosurgeon cannot remove excess, sparing vital brain tissue; secondly, the tumor is an uneven structure without clear boundaries, and it is unknown how many tumor cells have already penetrated into the tissues of a healthy brain. Radiation treatment and chemotherapy can only slow down the growth of the tumor, but not stop it.

The development of molecular methods allowed the study of gliomas at the level of genes. The result of the research was a change in the classification of the World Health Organization in 2016, which included the concept of key mutations for the development of gliomas of several genes. The classification has become more clear and based not on the visual characteristics of the tumor cells, but on their molecular characteristics.

But this did not greatly advance the treatment of the disease and did not improve the prospects for patients. Scientists around the world are creating international consortia to find a solution.

Demarcation of tumor boundaries

When surgical removal of the tumor is extremely important not to affect the vital areas of the brain. One of the advanced technologies is a brain surgery with the patient awakening during the removal of a tumor. There are no pain receptors in the brain, and local anesthesia is sufficient. The doctor during the operation talks with the patient and asks him to solve simple puzzles. Violation of patient behavior suggests that the doctor has invaded the danger zone. This approach allows the operation of tumors that were previously considered inoperable.

The development of Russian neurosurgeons and physicists who use the technique of intraoperative neuroimaging of gliomas can be considered a successful achievement in this field. Before the operation, 5-aminolevulinic acid (5-ALA) is administered orally to the patient, which is completely safe for humans since it is an intermediate product of metabolism in the body. This acid is converted to the fluorescent substance protoporphyrin IX.

It is surprising that this fluorescent substance accumulates in the tumor, making it visible when neurosurgeons use a special attachment to the surgical microscope. This technology allows you to remove the tumor as completely as possible.

MRI assistants

Today, the most significant technical breakthrough is observed in the field of pre-operative diagnosis of a tumor. Magnetic resonance imaging (MRI) allows to characterize the location and volume of the tumor before the operation. MRI with contrast enhancement is used in three projections and in three modes.

MRI spectroscopy is also used to assess the metabolism in the tumor and set the degree of anaplasia (loss of the external characteristics of the cell, according to which it can be attributed to any type), and MRI perfusion to determine the volume of blood passing through the tumor.

A very important study for the patient appeared - functional MRI mapping, which is necessary to determine the proximity of the motor, speech, and visual areas of the brain to the tumor. This is necessary so that the neurosurgeon can calculate how to remove the tumor by him, causing minimal damage to the patient.
Glioma classification

In 2007, the World Health Organization introduced the principle of classification of gliomas, dividing them according to the degree of malignancy and the characteristics of tumor cells into four groups, which were called degrees (Grade). The most benign I Grade, the most aggressive IV Grade, or in another way - glioblastoma. The classification used histological characteristics of tumor cells. In 2016, WHO introduces a new classification of gliomas, which requires, when making a diagnosis, to rely not only on the histological features of tumor cells, but also on the results of immunohistochemistry and FISH analysis and sequencing. It is required to evaluate the mutations of IDH1 / 2 and TP53, deletion of ATRX and co-deletion of 1p / 19q.

Radiation Surgery

But if, with all these approaches, the doctors do not take up the operation, they come to the aid of modern linear accelerators, such as cyberknife. A unique setting that gave rise to a new direction, combining surgery and radiation therapy. In fact, “cyberknife” is a radiosurgical effect on a tumor without invasive intervention.

Thanks to this installation, it became possible to “remove” a tumor that is located in inaccessible areas and previously would be inoperable. Numerous thin beams of radiation aimed at a tumor allow it to be destroyed or at least reduced with minimal impact on healthy areas of the brain.

Molecular tumor passport

But these achievements alone are not enough. Tumors are very different from each other at the genetic level. Modern molecular approaches have allowed gliomas to be characterized by a number of markers, but scientists are finding new genetic disorders that affect the sensitivity of the tumor to therapy. It is likely that after some time, WHO will propose a new classification of tumors, based on a larger sample of genetic disorders and more close to individual medicine.

In addition, there is a growing understanding that not only mutational studies of the patient's genome are important, but also attention should be paid to the transcript (the result of reading the genes in a given organism) and the proteome of tumor cells (a set of proteins synthesized as a result of reading their genome). They vary greatly and can serve as both a diagnostic factor and a therapeutic target. For example, it has been found that transcripts (RNA molecule) of known genes often change in a tumor, such a violation can lead to the production of an altered protein, or even to the fact that the protein will not be produced. These changes can serve to diagnose the degree of malignancy, and can also enter the prognostic signs panel.

New directions in the drug therapy of glioma

Modern chemotherapy drugs stimulate the death of tumor cells. But they also destroy normal actively dividing cells of the body, which worsens the general condition of the patient. At the same time, complete death of glioma tumor cells is not achieved. Such treatment does not allow the patient to extend the life for a long time. We need to look for new approaches. One of the vectors of such studies is targeted therapy, which increases the likelihood of the delivery of therapeutic killer molecules directly to the tumor cells. For example, there are developments in the use of nanoparticles that allow delivery of lower doses of toxic substances to glioma cells.

Another approach involves the use of oncolytic viruses, which can both stimulate apoptosis (figuratively speaking, forcing to suicide) tumor cells, and induce an immune response, which also leads to the death of tumor cells. Despite a number of disadvantages of this therapy, it is known that some of these viruses are already undergoing the first and second phases of clinical trials.

A new direction has emerged on the use of structured small molecules of DNA and RNA, called aptamers, which are intended to be used in the treatment of gliomas instead of antibodies, as well as for the diagnosis of tumors. And such developments are underway in our country. The membrane protein that is most characteristic of the tumor cell is selected, and a high-precision aptamer is selected (as the key to the lock). Such an aptamer can serve for therapy, diagnosis, and also for targeted delivery of another drug.

Not to mention the development of tumor immunotherapy, for which the Nobel Prize in Medicine in 2018 was awarded. Antibodies are being developed that are capable of causing the cells of the patient's own immune system to recognize the tumor and destroy it, like everything alien.

Understand the origins of gliomas

The new theory about the origin of gliomas from immature brain progenitor cells is very attractive. According to this theory, there is a small number of tumor stem cells (about 5%) in malignant tumors, which have infinite proliferative potential (ability to reproduce), and daughter cells, in which the number of divisions is limited. It is assumed that the daughter cells are more susceptible to chemotherapy and radiation exposure and die, thereby reducing the size of the tumor. And tumor stem cells, like queen bees in a hive, again restore their population after therapy. If you follow this theory, then you need to fundamentally change the approach to treatment and direct the whole therapy to these five percent of tumor stem cells.

Now it’s foolish to guess which approach will wreck the jackpot. It is necessary to develop all directions. The creation of gliomas biobanks, as well as the creation of gliomas cell culture banks, helps a lot in research. Bioinformatics approaches are also important, which can find patterns by analyzing large amounts of information about tumors. Technologies are developing rapidly, it is only necessary not to stop the massive attack on the monster in the brain from all sides.

He is not immortal.

Galina Pavlova, Doctor of Biological Sciences, Professor, Russian Academy of Sciences, Head of the Laboratory of Neurogenetics and Development Genetics, Institute of Gene Biology, Russian Academy of Sciences.

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